Scleroderma is a serious disease characterized by excessive accumulation of collagen and other connective tissue components in skin and external organs. The mechanisms responsible for such accumulation are not known. In previous work from our laboratories we have demonstrated that the TSK (tight skin) mutant mouse strain displays connective tissue abnormalities that closely resemble those present in the skin of patients with progressive systemic sclerosis (PSS) and we suggested that the TSK mice may be an ideal experimental model for the study of the connective tissue alteration in PSS. The purpose of the work proposed in this application will be to perform an in-depth and exhaustive study of the mechanisms responsible for the connective tissue alterations displayed by TSK mice. Particular emphasis will be placed on the study of the regulation of collagen synsthesis and degradation in TSK cultured fibroblasts applying State of the Art technology employing biosynthetic and biochemical methods as well as recently developed recombinant DNA techniques currently used in our laboratories. We will measure levels of functional and translatable mRNA and the rates of intracellular degradation of collagen in these cells. Biosynthesis of collagen in skin organ cultures and tissue cultures from normal and TSK dermal fibroblasts will be examined and the biosynthesized products will be characterized. Differences in the content or structure of the various components present in the tissues or synthesized in the TSK cultures will be identified. Special emphasis will be placed on the identification of the various collagen types present and in the quantitation of their relative proportions. Several other differences in the biological characteristics of normal and TSK cells and tissues will be explored in further detail. It is expected that the knowledge gained from these studies will be of direct relevance to understand the pathogenesis of the excessive collagen deposition characteristic of PSS and will permit a more rational approach to develop possible modes of therapy for this incurable and devastating disease.